Abnormalities of the cardiac excitation process that result in cardiac arrhythmias continue to be a major cause of death and disability. In spite of important recent advances in understanding this process (notably, at the molecular level of membrane ion-channels), the mechanisms that underlie arrhythmogenic activity remain incompletely understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcome in many cases. The overall objective of this project is to further the understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is the premise that understanding of mechanisms is imperative to the development of better treatment and prevention of sudden death. As in the previous period of support, the approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations. Specific aims are: (1) To develop a model of the cardiac ventricular action potential based on kinetic description of single ion channels. (2) To characterize, using this model, the cellular electrophysiologic consequences of channel-function alteration associated with the Long QT Syndrome. (3) To study the ionic basis of myocardial cellular heterogeneity and its electrophysiologic consequences. (4) To study the effects of regional tissue inhomogeneties (in membrane excitability or tissue architecture) on action potential propagation. (5) To characterize the properties of reentrant propagation and the processes of initiation and termination of reentry in the anisotropic myocardium.